The overall goal of this program is to define mechanisms that contribute to and protect against vascular disease. The primary focus is on the impact of cardiovascular risk factors on the cerebral circulation. This Program continues to evolve and successfully integrate emerging molecular techniques with more traditional approaches to examine mechanisms that regulate the structure and function of the vessel wall under normal conditions and in models of disease. The program has several well-defined themes: 1) the impact of cardiovascular risk factors on the vasculature, 2) the importance of oxidative stress in models of vascular disease and stroke, and 3) mechanisms of vascular protection. Modern molecular and mechanistic approaches will be used to examine effects of aging, hypertension, and hyperhomocysteinemia on cerebral blood vessels. We will examine novel and interrelated mechanisms, including the role of reactive oxygen species in intracranial hemorrhage during hypertension, as well vascular dysfunction during aging and hyperhomocysteinemia. Molecular and functional studies are proposed to examine the role of superoxide dismutases and peroxisome proliferator activated receptor-gamma in protecting against intracranial hemorrhage during hypertension, and protecting the vasculature during hyperhomocysteinemia and aging. The program has multiple strengths. First, the investigators have an established record of synergistic and highly productive interaction with a commitment to studies of the cerebral circulation. Second, strong new investigators with key expertise have been integrated into the program. Third, the investigators use diverse and state-of-the-art approaches along with sophisticated methodology. For example, some of the animals used express variants in human genes, allowing the study of vascular consequences in 'humanized' mice, a powerful tool combining human genetics with mechanistic vascular studies. Fourth, the investigators are leaders in several areas of study: cerebral circulation, endothelium, nitric oxide, oxidative stress, vascular protection, vascular structure, and studies of the impact of cardiovascular risk factors on cerebral vascular biology. The program consists of three projects supported by an administrative core and a transgenic and knockout animal core. This highly integrated, multidisciplinary approach should continue to facilitate rapid progress and novel insight into mechanisms that impact cerebral blood vessels in pathophysiology. A better understanding of these mechanisms should provide insight into approaches that could delay, or even halt the progression of cerebral vascular disease - a major contributor to stroke and dementia.